ABSTRACT: The scavenger receptor CD36 has lipid and non-lipid ligands and versatile functions in metabolism and immunity. An important function of CD36 is its ability to transduce intracellular signals triggered by its ligands. CD36 signaling contributes to the regulation of several aspects of fatty acid (FA) utilization such as fat taste perception, chylomicron production, enteroendocrine secretion, FA oxidation etc. We recently showed that CD36 interacts with the AMPK and insulin signaling pathways and we propose that this mediates an important part of its actions on nutrient utilization. We document presence of CD36 in a molecular complex with insulin receptor beta (IR?) and CD36-mediated recruitment to IR? of Fyn and the catalytic p85 subunit of PI3-kinase. We also find that palmitic acid binding to CD36 interferes with Fyn and p85 recruitment and blunts Akt phosphorylation. In this project, which involves a multidisciplinary collaboration between basic and clinical scientists, we will test the novel hypothesis that the membrane protein CD36 via its interaction with the PI3K pathway influences endothelial cell function, insulin?s action on microvasculature recruitment and consequently nutrient flux and the effect of high fat feeding to cause endothelial dysfunction. Our preliminary data document diminished vascular compliance in CD36-/- mice and more importantly in African Americans carrying coding SNP rs3211938 that reduces CD36 level by 50%. We will examine the functional implications of CD36 signaling in endothelial cells and the consequences of endothelial cell CD36 deletion in mice on vascular function and insulin regulation of tissue perfusion and energetics. We will determine in these mice the effect of high fat feeding to induce endothelial dysfunction and whether this is reversed by treatment with phosphodiesterase 5 (PDE5) inhibition which blocks cGMP degradation. In a parallel approach we will examine influence of partial CD36 deficiency in African American carriers of rs3211938 on endothelial dysfunction, microvascular recruitment by insulin and the efficacy of PDE5 inhibition treatment. Obesity and endothelial dysfunction are highly prevalent especially in African Americans and associate with negative cardiovascular and metabolic outcomes. The proposed work will provide fundamental information that is currently unavailable and that could influence treatment of endothelial dysfunction and insulin resistance in humans.